Diabetes and hypertension are the leading causes of endstage renal disease (ESRD). Despite effective medications, the incidence of ESRD is increasing and the associated costs now exceed $15 billion a year. The renal expression of TGF-beta is elevated in hypertension and diabetes and blockade of this pathway decreases renal fibrosis. However, the factors that increase the production of TGF-beta and its role in the initiation of renal disease remain to be determined. In preliminary experiments, we found that inducing the renal formation of 20-HETE or blocking the actions of TGF-beta attenuate the development of renal disease in Dahl S rats. TGF-beta also directly increased the permeability of glomeruli to albumin (Palb) and inhibited the glomerular formation of 20-HETE. Thus, this proposal will evaluate the hypothesis that a deficiency in the renal formation of 20-HETE leads to elevations in glomerular capillary pressure (Pgc) and the renal expression of TGF-beta in Dahl S rats and that the increase in TGF-beta triggers the development of proteinuria and renal disease by increasing Palb. Specific Aim 1 will determine the relationships between Pgc, the renal expression of TGF-beta, Palb and the development of renal disease and the effects of servocontrol of renal perfusion pressure (RPP) on these responses. Specific Aim 2 will determine if the reduced production of 20-HETE contributes to the increases in Pgc, TGF-beta and the development of renal disease. Specific Aim 3 will examine the interactions between TGF-beta and 20-HETE in the regulation of Palb and the mechanism by which TGF-beta inhibits the formation of 20-HETE. Specific Aim 4 will determine whether Palb is altered early in the development of hypertension and the role of TGF-beta in mediating this response. These studies will employ an array of techniques, ranging from direct measurement of Pgc, LC/MS measurement of 20-HETE and chronic servocontrol of RPP to measurements of Palb and Ca++ in isolated glomeruli. They will also utilize a newly-developed congenic strain of Dahl S rats in which renal 20-HETE levels are elevated and novel inhibitors and antibodies that can manipulate the 20-HETE and TGF-beta pathways in vivo. These translational studies will provide important new information on the role of TGF-beta, 20-HETE and Pgc in the pathogenesis of hypertension-induced renal disease and may be applicable to diabetes and other models of renal disease as well in which TGF-beta and Pgc are also elevated.